Acetylcholinesterase loosens the brain's cholinergic anti-inflammatory response and promotes epileptogenesis

Abstract

Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh) release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunctions are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE) and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT) and transgenic mice over-expressing the “synaptic” splice variant AChE-S (TgS). One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust up-regulation of AChE as early as 48 h following pilocarpine-induced status epilepticus (SE). AChE was expressed in hippocampal neurons, microglia, and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 h after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.

Neural circuitry and immunity

“…Brain cholinergic mAChR-mediated signaling also has an important role in the regulation of peripheral cytokine responses and inflammation [6,32,64]. In addition, experimental evidence indicates that brain cholinergic signaling regulates local brain inflammatory responses [123–126] and the brain cholinergic system is affected in peripheral inflammatory and metabolic conditions [110,127–129]. Sepsis is a lethal disorder with peripheral immune and metabolic dysregulation and neuropsychiatric manifestations.…”

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

“…Cholinergic functions are altered in the epileptic temporal lobe, however, the exact role and nature of these changes in the pathogenesis of the disease are still as yet to be understood (Friedman et al, 2007). Cholinergic dysfunction (for review see Friedman et al, 2007) and acetylcholine-esterase (AChE) upregulation (Zimmerman et al, 2008) have been observed in the epileptic temporal lobe, however, the exact role of these changes in the pathogenesis of the disease are only recently demonstrated by Gnatek et al (2012). AChE mRNA and protein levels are fast and strongly increased after SE in mice hippocampus (Gnatek et al, 2012), probably as an initial attempt to maintain homeostasis by reducing ACh levels and subsequently neuronal excitability (Meshorer et al, 2005).…”

“…Cholinergic dysfunction (for review see Friedman et al, 2007) and acetylcholine-esterase (AChE) upregulation (Zimmerman et al, 2008) have been observed in the epileptic temporal lobe, however, the exact role of these changes in the pathogenesis of the disease are only recently demonstrated by Gnatek et al (2012). AChE mRNA and protein levels are fast and strongly increased after SE in mice hippocampus (Gnatek et al, 2012), probably as an initial attempt to maintain homeostasis by reducing ACh levels and subsequently neuronal excitability (Meshorer et al, 2005). Upregulated AChE mRNA was found in principle and inhibitory interneurons, endothelial cells and activated microglia (Gnatek et al, 2012).…”

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

“…ACh-related mechanisms are widely involved in, and sufficient for, generating epileptic seizures (56), with cholinergic imbalances hallmarking several epileptic syndromes (57) and cholinergic agonists inducing limbic seizures (58). Recent independent reports implicated miRs in both initiating and changing the response to seizure-inducing agents (59), but did not explore the putative regulatory role of miRs controlling neuronal cholinergic transmission (57) in avoiding such seizures and affecting the susceptibility to epilepsy.…”